Pregnancy is associated with changes in immune function which may protect the fetus from harmful maternal immune responses, but which also increase maternal susceptibility to infections and can exacerbate or alleviate particular autoimmune diseases. This proposal will use the influenza virus A/PR/8/34 hemagglutinin (PR8 HA) as a well characterized model antigen with which to determine factors modulating the immune responses to viral, maternal and fetal antigens during murine pregnancy. The following specific questions will be addressed: 1) How do pregnancy-associated changes in immune function modulate maternal immune responses to influenza virus? The specific aspects of anti-viral immunity that are suppressed or enhanced during pregnancy will be determined by comparing pregnant and non-pregnant BALB/c mice for their abilities to generate influenza virus-specific immune responses. How pregnancy affects the capacity of influenza virus-specific T helper (Th) cells to differentiate into distinct phenotypes (e.g. Th1 versus Th2 cells) will be examined using transgenic (Tg) mice expressing HA-specific T cell receptors (TCR Tg mice). 2) Does pregnancy affect autoreactivity to influenza HA as a maternal self antigen? Whether pregnancy influences the magnitude of autoreactive HA-specific T and/or B cell responses will be examined in mice that express the HA as a neo-self antigen (HA Tg mice). In addition, the extent to which maternal anti-HA (self) Th responses in HA Tg mice are suppressed or modified (either systemically, or in lymph nodes draining the uterus) during pregnancy will be determined. 3) How does the maternal immune system perceive the HA as a fetal antigen? Female BALB/c mice will be mated with male HA Tg mice, and the ability of the fetal HA either to activate or to induce antigen-specific tolerance among maternal HA-specific T and/or B cells will be analyzed. Whether expression in different fetal cell types affects how the HA is perceived by the maternal immune system will be evaluated. How the induction of anti-viral immune responses can be harmful to fetal development will also be assessed. By defining mechanisms by which the maternal immune system accommodates the fetal allograft, these studies may provide clinical benefits in the areas of transplantation and autoimmunity. Determining the effects of pregnancy on immune responses to viral and self antigens, and the effects of maternal immunity on fetal development, may similarly benefit women's health and child development.